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The small GTPase RhoU lays downstream of JAK/STAT signaling and mediates cell migration in multiple myeloma
Multiple myeloma is a post-germinal center B-cell neoplasm, characterized by the proliferation of malignant bone marrow plasma cells, whose survival and proliferation is sustained by growth factors and cytokines present in the bone marrow microenvironment. Among them, IL-6 triggers the signal downst...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811530/ https://www.ncbi.nlm.nih.gov/pubmed/29440639 http://dx.doi.org/10.1038/s41408-018-0053-z |
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author | Canovas Nunes, Sara Manzoni, Martina Pizzi, Marco Mandato, Elisa Carrino, Marilena Quotti Tubi, Laura Zambello, Renato Adami, Fausto Visentin, Andrea Barilà, Gregorio Trentin, Livio Manni, Sabrina Neri, Antonino Semenzato, Gianpietro Piazza, Francesco |
author_facet | Canovas Nunes, Sara Manzoni, Martina Pizzi, Marco Mandato, Elisa Carrino, Marilena Quotti Tubi, Laura Zambello, Renato Adami, Fausto Visentin, Andrea Barilà, Gregorio Trentin, Livio Manni, Sabrina Neri, Antonino Semenzato, Gianpietro Piazza, Francesco |
author_sort | Canovas Nunes, Sara |
collection | PubMed |
description | Multiple myeloma is a post-germinal center B-cell neoplasm, characterized by the proliferation of malignant bone marrow plasma cells, whose survival and proliferation is sustained by growth factors and cytokines present in the bone marrow microenvironment. Among them, IL-6 triggers the signal downstream of its receptor, leading to the activation of the JAK/STAT pathway. The atypical GTPase RhoU lays downstream of STAT3 transcription factor and could be responsible for mediating its effects on cytoskeleton dynamics. Here we demonstrate that RHOU is heterogeneously expressed in primary multiple myeloma cells and significantly modulated with disease progression. At the mRNA level, RHOU expression in myeloma patients correlated with the expression of STAT3 and its targets MIR21 and SOCS3. Also, IL-6 stimulation of human myeloma cell lines up-regulated RHOU through STAT3 activation. On the other hand, RhoU silencing led to a decrease in cell migration with the accumulation of actin stress fibers, together with a decrease in cyclin D2 expression and in cell cycle progression. Furthermore, we found that even though lenalidomide positively regulated RhoU expression leading to higher cell migration rates, it actually led to cell cycle arrest probably through a p21 dependent mechanism. Lenalidomide treatment in combination with RhoU silencing determined a loss of cytoskeletal organization inhibiting cell migration, and a further increase in the percentage of cells in a resting phase. These results unravel a role for RhoU not only in regulating the migratory features of malignant plasma cells, but also in controlling cell cycle progression. |
format | Online Article Text |
id | pubmed-5811530 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-58115302018-02-14 The small GTPase RhoU lays downstream of JAK/STAT signaling and mediates cell migration in multiple myeloma Canovas Nunes, Sara Manzoni, Martina Pizzi, Marco Mandato, Elisa Carrino, Marilena Quotti Tubi, Laura Zambello, Renato Adami, Fausto Visentin, Andrea Barilà, Gregorio Trentin, Livio Manni, Sabrina Neri, Antonino Semenzato, Gianpietro Piazza, Francesco Blood Cancer J Article Multiple myeloma is a post-germinal center B-cell neoplasm, characterized by the proliferation of malignant bone marrow plasma cells, whose survival and proliferation is sustained by growth factors and cytokines present in the bone marrow microenvironment. Among them, IL-6 triggers the signal downstream of its receptor, leading to the activation of the JAK/STAT pathway. The atypical GTPase RhoU lays downstream of STAT3 transcription factor and could be responsible for mediating its effects on cytoskeleton dynamics. Here we demonstrate that RHOU is heterogeneously expressed in primary multiple myeloma cells and significantly modulated with disease progression. At the mRNA level, RHOU expression in myeloma patients correlated with the expression of STAT3 and its targets MIR21 and SOCS3. Also, IL-6 stimulation of human myeloma cell lines up-regulated RHOU through STAT3 activation. On the other hand, RhoU silencing led to a decrease in cell migration with the accumulation of actin stress fibers, together with a decrease in cyclin D2 expression and in cell cycle progression. Furthermore, we found that even though lenalidomide positively regulated RhoU expression leading to higher cell migration rates, it actually led to cell cycle arrest probably through a p21 dependent mechanism. Lenalidomide treatment in combination with RhoU silencing determined a loss of cytoskeletal organization inhibiting cell migration, and a further increase in the percentage of cells in a resting phase. These results unravel a role for RhoU not only in regulating the migratory features of malignant plasma cells, but also in controlling cell cycle progression. Nature Publishing Group UK 2018-02-13 /pmc/articles/PMC5811530/ /pubmed/29440639 http://dx.doi.org/10.1038/s41408-018-0053-z Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Canovas Nunes, Sara Manzoni, Martina Pizzi, Marco Mandato, Elisa Carrino, Marilena Quotti Tubi, Laura Zambello, Renato Adami, Fausto Visentin, Andrea Barilà, Gregorio Trentin, Livio Manni, Sabrina Neri, Antonino Semenzato, Gianpietro Piazza, Francesco The small GTPase RhoU lays downstream of JAK/STAT signaling and mediates cell migration in multiple myeloma |
title | The small GTPase RhoU lays downstream of JAK/STAT signaling and mediates cell migration in multiple myeloma |
title_full | The small GTPase RhoU lays downstream of JAK/STAT signaling and mediates cell migration in multiple myeloma |
title_fullStr | The small GTPase RhoU lays downstream of JAK/STAT signaling and mediates cell migration in multiple myeloma |
title_full_unstemmed | The small GTPase RhoU lays downstream of JAK/STAT signaling and mediates cell migration in multiple myeloma |
title_short | The small GTPase RhoU lays downstream of JAK/STAT signaling and mediates cell migration in multiple myeloma |
title_sort | small gtpase rhou lays downstream of jak/stat signaling and mediates cell migration in multiple myeloma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811530/ https://www.ncbi.nlm.nih.gov/pubmed/29440639 http://dx.doi.org/10.1038/s41408-018-0053-z |
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